Candidate's Plans/Training: The candidate plans a career as an independent clinical investigator focusing on patient oriented research related to hematologic, vascular and cardiac determinants of cardiovascular/cerebrovascular disease. Training will include formal epidemiological course work in clinical research and closely mentored completion of the research protocol. Environment: The Cardiology Division and Department of Public Health at Weill Cornell Medical College will provide structured mentoring. The Echocardiography Laboratory, Department of Public Health, and General Clinical Research Center at the New York Presbyterian Hospital will provide research support. Coursework will be undertaken at the Columbia School of Public Health. Research: Ischemic stroke constitutes a public health burden of staggering proportions, yet its cause often cannot be determined despite thorough evaluation. Although patent foramen ovale (PFO) has been identified as a risk factor for unexplained stroke in younger patients, the overwhelming majority of PFOs are not pathogenic. Potentially key co-determinants of PFO pathogenicity have emerged with recent identification of a host of venous prothrombotic factors that could heighten the risk of paradoxical embolization. Various arterial procoagulant factors could also explain an important fraction of cryptogenic strokes, through mechanisms independent of PFO. There is evidence that venous and arterial thrombophilias may be important risk factors for ischemic stroke, especially in young subjects. Their significance in populations with unexplained stroke, however, has not been sufficiently studied. Involvement of thrombophilias in the etiology of cryptogenic stroke would not only illuminate the mechanism of disease, but would also help define appropriate therapeutic strategies. These are of immense importance because there are limited data to guide the decision to institute life-long anticoagulation, surgical closure of PFO, or indefinite antithrombotic therapy for such patients. We propose a prospective case-control study to examine whether 1) venous thrombophilias are independent risk factors for cryptogenic stroke; 2) venous thrombophilias are important co-determinants of PFO pathogenicity; and 3) arterial thrombophilias have a prominent role in explaining cryptogenic stroke. Interactions among thrombophilias, thrombophilias and traditional cardiovascular risk factors, and thrombophilias and other potential cardiac sources of embolism will also be investigated.